Colonic release compostion

ABSTRACT

The present invention relates to an improved controlled (preferably delayed) release formulation for delivery of prednisolone sodium metasulphobenzoate. The formulation comprises prednisolone sodium metasulphobenzoate surrounded by a coating comprising glassy amylose, ethyl cellulose and dibutyl sebacate, wherein the ratio of amylose to ethyl cellulose is from (13.5) to (1:4.5) and wherein the amylose is corn or maize amylose.

The present invention relates to an improved controlled (preferablydelayed) release formulation for delivery of prednisolone sodiummetasulphobenzoate. The formulation comprises prednisolone sodiummetasuiphobenzoate surrounded by a coating comprising glassy amylose,ethyl cellulose and dibutyl sebacate, wherein the ratio of amylose toethyl cellulose is from 1:3.5 to 1:4.5 and wherein the amylose is cornor maize amylose.

The colon can be a site for the local action and/or, potentially, thesystemic absorption of therapeutic agents. Another advantage is thatactives can be selectively taken up in the colon. The delivery of drugsdirectly to their site of action in the treatment of diseases such asinflammatory bowel diseases (IBD), can increase their efficacy andreduce unpleasant and/or serious side effects that result from systemicabsorption.

There are a number of systems that attempt to deliver drugs to thecolon. In general, these are limited in their performance and/orspecificity and can be characterised as

-   -   rectally-delivered foams and enemas    -   pH-triggered, oral delivered systems    -   pro-drugs which are activated in the colon    -   time-dependent oral delivered systems.

The site of activity of rectally administered products is generallylimited to the rectum and distal colon, and patient acceptability is aproblem.

Orally delivered products that rely on pH and/or timedependent-mechanisms for drug release are inherently unreliable inattaining consistent colon-specific delivery in patients. This is due tothe wide variability in transit times and pH differentials in thevarious parts of the gut.

The recent development of oral delivery systems that use bacterialenzymes to trigger the release of actives offers the potential toovercome many of the problems experienced with the earlier systems.

In WO 91/07949, a delayed release formulation is described for generalapplication in targeting medicaments and diagnostic agents into thecolon.

However, this document does not take into account, or teach, thatdifferent actives can have individual formulations to obtain the optimumtargeting to the desired site and absorption profiles. Since medicinalactives differ in a number of biochemical and biophysicalcharacteristics, such as absorption, polarity, solubility and logp, itmay be possible to provide individual formulations which provide suchoptimisation.

The present invention provides such a formulation for the activeprednisolone sodium metasulphobenzoate.

Prednisolone sodium metasulphobenzoate is a corticosteroid, known forits use in treating Inflammatory Bowel Disease (IDB). It is generallypoorly absorbed from the upper gastrointestinal tract and is currentlyadministered rectally as a topical formulation. This is often unpleasantand unpopular with patients. It is also difficult to control dosedelivery and only the distal part of the colon can be reached.

The present invention provides a novel formulation for improvedcontrolled release of an oral dose of prednisolone sodiummetasulphobenzoate.

A first aspect of the invention provides a controlled releaseformulation comprising prednisolone sodium metasulphobenzoate surroundedby a coating comprising glassy amylose, ethyl cellulose and dibutylsebacate. The amylose and the ethyl cellulose are plasticised with thedibutyl sebacate. The ratio of amylose to ethyl cellulose is from 1:3.5to 1:4.5. The amylose is corn or maize derived. The controlled releaseformulation is preferably delayed release.

This formulation provides an advantageous delivery of the prednisolonesodium metasulphobenzoate to the colon. The delivery of prednisolonesodium metasulphobenzoate is coincident with the arrival of the dosageform in the colon.

The characteristics of glassy amylose are well known and are described,e.g. in WO 91/07949. As described in WO 91/07949 and as applicable tothe present invention, the glassy amylose preferably has a Tg of notless than 20° C. below the temperature at which the use of thecomposition is carried out. This temperature (at which the compositionis used) will usually be body temperature, i.e. 37° C. The Tg is thuspreferably around 17° C. or more. It may be around 25° C. or more,around 30° C. or more, or 35° C. or more. Controlling the amount ofwater in the amylose composition predetermines the Tg. This can becarried out by a number of procedures known in the art, such as theconcentration of amylose in the solution as well as spraying and dryingof the resulting product.

The amylose may be prepared by any technique known in the art, such asby forming a gel from an aqueous solution and then drying or by spraydrying.

The resulting dry glassy amylose can be further processed. It may bemelted (in the form of a slab) or may first be powdered or granulated.After such melting, the amylose can be used to coat pellets, or otherforms, of active ingredient.

Typically, the amylose is 1 to 15%, preferably 2 to 10%, or 3 to 5% ofthe solution (on a weight by weight basis). As described below, thesolution may be aqueous or an aqueous-alcohol mix.

The glassy amylose is part of the coating, in combination with ethylcellulose and dibutyl sebacate. Typically, a solution of around 15 to20% ethyl cellulose is admixed with the other ingredients. The finalrange of ethyl cellulose in the coating product is usually in the rangeof from 2 to 15%, preferably from 5 to 10% on a weight by weight basis.

The amylose, ethyl cellulose and dibutyl sebacate are preferably admixedbefore applying to the prednisolone sodium metasulphobenzoate.

It is preferable that the glassy amylose comprises as little moisture aspossible. It should be lower than 20% (w/w), more preferably lower than15% (w/w).

It has been determined that the particular combination of glassyamylose, ethyl cellulose and dibutyl sebacate provides the optimumcolonic delivery formulation for prednisolone sodium metasulphobenzoate.It is thus preferred that the presence of any other ingredient in thecoating is minimised to no more than 10% (w/w). Furthermore, any hydroxygroup in derivative form, of the amylose, should be limited to no morethan 10% of the hydroxy groups present. A convenient test for the purityof amylose can be found in Banks et al, Starke, 1971, 23,118.

The preferred ratios of the three components are, on a weight by weightbasis of: glassy amylose:ethyl cellulose:dibutyl sebacate 1:3.5 to4.5:0.5 to 1.5 1:3.5 to 4.5:0.8 to 0.9 1:3.5 to 4.5:0.85 1:4:0.85

Suitable dosage forms of the present invention include-prednisolonesodium metasulphobenzoate (expressed as prednisolone) at 20 mg, 40 mg,60 mg, 80 mg, 100 mg or 120 mg (per day). An example of a suitable rangeof from 40 mg to 120 mg per day can be used for treatment. An example ofa suitable range of from 40 to 60, 70, 80 or 100 mg per day can be usedfor prevention and/or treatment of inflammatory bowel disease. Byprevention, we particularly include maintenance of remission.

The prednisolone sodium metasulphobenzoate is usually admixed with afiller. The filler may be any suitable agent, for example comprising orconsisting of one or more of lactose, mannitol, sorbitol, xylitol,starch, or a cellulose derivative. In the present invention, the fillerpreferably is or comprises mannitol or lactose. The mannitol preferablyhas a mean particle size of around 85-90 μm and a bulk density of around0.66 gcm⁻³. The lactose preferably has a mean particle size such that95% of particles are less than 45 μm. Preferably the lactose has a bulkdensity of around 0.47 gcm⁻³. The mannitol or lactose preferably presentin the range of ratios from 1:5 to 1:2 with the prednisolone sodiummetasulphobenzoate. This “core” comprising the active ingredient, mayalso comprise microcrystalline cellulose, in order to optimise extrusionand spheronisation. The ratio of microcrystalline cellulose toprednisolone sodium metasulphobenzoate is in the range of 1:2.5 to1:0.5, preferably 1:2.5 to 1:1.1, preferably approximately 1:1.2.

The formulation of the present invention is most preferably in the formof pellets, tablets, mini-tabs or capsules. In each formulation, thecoating thickness equates to around 15% to 25% of the total weight ofthe formulation. The pellet formulation may range in size, for examplefrom 0.5 to 1.5 mm in diameter.

In the present invention, dibutyl sebacate has been determined toprovide an optimum combination of plasticiser function and drug release.In the selection of plasticiser, dibutyl sebacate was found to bepreferable as follows:—

A plasticiser of fractionated coconut oil resulted indiffusion/digestion problems. A plasticiser of dibutyl sebacatecontaining silica provided too high a diffusion element of thediffusion/digestion release profile. Use of dibutyl sebacate was used toprovide optimum functionality of digestion and minimised drug diffusionprior to digestion of the coat.

The formulation according to the invention may be within a capsule. Sucha capsule may be any known in the art, such as a capsule comprising oneor more of gelatin, starch or hydroxypropylmethyl cellulose.

The second aspect of the invention provides a process for producing aformulation according to the first aspect of the invention. Any processknown in the art can be used. As described above, glassy amylose mustfirst be prepared. This anylose can then be applied to the active “core”in layers or otherwise. Preferably, the amylose is admixed with theethyl cellulose and dibutyl sebacate before applying to the active“core”. Dry glassy amylose can be melted in the form of a slab or filmor can first be granulated or powdered. The melted amylose is then mixedwith the ethyl cellulose and dibutyl sebacate before being applied tothe active “core”. Alternatively, an aqueous alcoholic or an aqueoussolution of amylose, is optionally admixed with ethyl cellulose anddibutyl sebacate and can be applied to the active “core”. In thisprocess, the concentration of amylose in the solution is usually in theregion of 1 to 15%, or preferably 1 to 10%, or most preferably 1 to 5%(weight by weight). Typically, the coating is applied to the active byspraying or dipping. Suitable spraying and dipping machines are wellknown in the art and can be used in the process of the presentinvention.

In particular, ethyl cellulose in aqueous media is applied directly to a20% amylose suspension in aqueous ammonia. Mixtures of ethyl celluloseand amylose are preferably prepared by mixing in the ratio of 4:1 withthe temperature maintained above 60° C. during the coating process. Theresulting product is dried for one hour at 60° C.

A process as described in WO 99/21536 can also be used in the presentinvention. This method provides contacting the active “core” with asolution of the coating composition in a solvent system comprising bothwater and a water miscible organic solvent. The water miscible organicsolvent being capable, on its own, of dissolving ethyl cellulose. Thewater and organic solvent are then removed. The solvent system shouldcontain at least 50% weight by weight organic solvent. Contrary to theprocess described in WO 99/21536, the proportion of amylose tofilm-forming polymer can be any of those described in the presentinvention. In this process, the temperature can be any ranging from 20°C. upwards, in particular in the range of 20° C. to 50° C. or 60° C.,although a temperature of over 60° C. can also be used. Again,application of the coating to the active material is preferably byspraying or by dipping, although the process is not limiting.

Furthermore, a process as described in WO 99/25325 can be used accordingto the present invention. This method provides a method of coatingactive material with a coating comprising an aqueous dispersion of anamylose alcohol mix, ethyl cellulose and a plasticiser at a temperatureof less than 60° C. The coating, preferably contains between 1 and 15%weight by weight of amylose alcohol mix. The coating compositions areprepared by admixing an aqueous dispersion of an amylose alcohol mixwith an aqueous dispersion of the ethyl cellulose and dibutyl sebacate.Usually, the aqueous dispersion of the ethyl cellulose ispre-plasticised by rapid, sheer mixing with an aqueous dispersion of theplasticiser. Alternatively, the ethyl cellulose and the plasticiser canbe directly mixed. The aqueous dispersion of the amylose alcohol mix ispreferably a dispersion of an amylose butanol mix. Usually, theconcentration of the amylose butanol mix in a dispersion is in the rangeof 1 to 15% weight by weight of the final dispersion.

Following application of the coating to the active “core”, thecomposition is dried. The formulation can be allowed to dry in air or inan inert atmosphere. Alternatively, the formulation can be dried bycuring. The curing may be carried out at a temperature of between 5° C.and 60° C. over a period of up to 6 hours, preferably around 1 hour atapproximately 60° C. Longer curing times are preferably avoided as thesemay result in crystalline regions within the coating. Shorter curingtimes ensure that the amylose is retained in the glassy form. Aftercuring, the final products are preferably packaged such that they areprotected from moisture.

All preferred features of the first aspect of the invention, also applyto the second aspect.

A third aspect of the present invention provides a formulation accordingto the first aspect of the invention, for use in the prevention ortreatment of inflammatory bowel disease. In the present invention,inflammatory bowel disease includes Crohn's colitis and ulcerativecolitis.

In the present invention, “prevention” includes maintaining a patient ina disease free state or maintaining a patient with low-level (egtolerable) symptoms.

All preferred features of the first and second aspects also apply to thethird aspect.

In a fourth aspect of the invention, there is provided the use of glassyamylose, ethyl cellulose, dibutyl sebacate and prednisolone sodiummetasulphobenzoate, in the manufacture of a medicament for theprevention or treatment of inflammatory bowel disease.

All preferred features of the first to third aspects of the inventionalso apply to the fourth aspect.

The present invention refers to the following Figures:

FIG. 1: Plasma prednisolone drug levels after administration of coatedprednisolone sodium metasulphobenzoate (equivalent to 60 mgprednisolone).

Each point is the mean±standard error of the mean for seven subjects.

FIG. 2: Plasma prednisolone drug levels in Subject 2 afteradministration of coated prednisolone sodium metasulphobenzoate(equivalent to 60 mg prednisolone), showing drug release when thepellets are localised in the colon.

FIG. 3: Plasma prednisolone drug levels after administration ofprednisolone sodium metasulphobenzoate (equivalent to 60 mgprednisolone), in different coatings.

FIG. 4: Plasma prednisolone drug levels after administration ofprednisolone sodium metasulphobenzoate (equivalent to 60 mgprednisolone), in fed and fasted subjects.

The present invention is now described with reference to the following,non-limiting examples.

EXAMPLES Example 1

Pellet Production—Lactose Filler

Pellets of prednisolone sodium metasulphobenzoate, microcrystallinecellulose and lactose (47% prednisolone sodium metasulphobenzoate, 40%microcrystalline cellulose, 13% lactose) were reliably and efficientlyproduced by a process of extrusion through a die or mesh, followed byspheronisation, achieved through breakage and rounding on a hatchedplate, rotating in a cylinder. Successful extrusion-spheronisationrequired the production of a cohesive wet mass which flowed through thedie without adhering to the extruder or to itself, whilst retaining adegree of rigidity so that the shape imposed by the die is retained.Furthermore the extrudate must be brittle enough to break into uniformlengths on the spheronisation plate, yet still be plastic enough toround into spherical pellets.

The pellets produced had an acceptable appearance, strength, friabilityand release characteristics.

Delayed Release Formulation Production

A mixed polymer suspension containing maize amylose, ethyl cellulose anddibutyl sebacate (in the ratio of 1:4:0.85) was heated to convert theamylose into its amorphous form. The resulting solution was sprayed intothe top of a fluidised bed of the pellets prepared above (lactosefiller), until a 20% total weight gain was obtained.

The coated product was then cured for approximately 1 hour at 60° C., inair. The coated pellets were filled into a hard gelatin capsule.

Example 2

Pellet Production—Mannitol Filler

Pellets of prednisolone sodium metasulphobenzoate, microcrystallinecellulose and mannitol (47% prednisolone sodium metasulphobenzoate, 40%microcrystalline cellulose, 13% mannitol) were reliably and efficientlyproduced by a process of extrusion through a die or mesh, followed byspheronisation, achieved through breakage and rounding on a hatchedplate, rotating in a cylinder. Successful extrusion-spheronisationrequired the production of a cohesive wet mass which flowed through thedie without adhering to the extruder or to itself, whilst retaining adegree of rigidity so that the shape imposed by the die is retained.Furthermore the extrudate must be brittle enough to break into uniformlengths on the spheronisation plate, yet still be plastic enough toround into spherical pellets.

The pellets produced had an acceptable appearance, strength, friabilityand release characteristics consistent with colon targetting.

Delayed Release Formulation Production

A mixed polymer suspension containing maize amylose, ethyl cellulose anddibutyl sebacate (in the ratio of 1:4:0.85) was heated to convert theamylose into its amorphous form. The resulting solution was sprayed intothe top of a fluidised bed of the pellets prepared above (mannitolfiller), until a 20% total weight gain was obtained.

The coated product was then cured for approximately 1 hour at 60° C., inair. The coated pellets were filled into a hard gelatin capsule.

Example 3

Phase I Study of Colon Targeting

Using pellets described in Example 1.

Four phase I studies have been completed. In the first of these, anethyl cellulose to amylose ratio of 5:1 was used with a 10% weight gain.The second and third studies, investigated the effect of a thicker coat(20% weight gain) at a 4:1 ethylcellulose to amylose ratio. All otherfeatures of the comparison formulation were the same.

Capsules containing coated pellets of prednisolone sodiummetasulphobenzoate, equivalent to 60 mg prednisolone, were administeredto seven healthy, fasted volunteers. Progress of the dose through thegastrointestinal tract was followed over 24 hours by gamma-scintigraphyafter the co-administration of ethylcellulose coated ¹¹¹indium labellednon-pareils. Plasma levels of prednisolone were determined at varioustime points up to 48 hours after administration. Excreted drug pelletswere harvested over five days and residual drug levels determined.

Plasma prednisolone levels appeared at around two hours after dosing,rising to a maximum at between five and six hours. The mean C_(max) waslower than those reported in two of three patients following treatmentwith a 60 mg prednisolone metasulphobenzoate enema and the data weregenerally rather less variable than those reported by McIntyre et al(1985). Although the mean AUCs were higher than reported by McIntyre etal, they were substantially lower than those reported for oraladministration of lower doses. Comparison of prednisolone C_(max) andAUC from the formulation with conventional oral and rectal formulationsof the metasulphobenzoate and with the 21-phosphate given rectally.Study Compound Dose, route C_(max) AUC Study 1 Prednisolone 60 mg, oral168 ± 56 1441 ± 541 Amylose:Ethlycellulose metasulphobenzoate 1:5 10%Weight Gain McIntyre et al Prednisolone 60 mg, rectal 147 ± 79  632 ±509 1985 metasulphobenzoate Prednisolone-21-phosphate 20 mg, rectal 148± 75  599 ± 310 Flouvat et al 1991 Prednisolone 40 mg, oral 242 ± 582189 ± 475 metasulphobenzoate

The data indicate that this formulation is targeted to the proximalcolon, although the plasma concentrations are substantially lower thanthose reported for conventional oral dose forms.

The plasma-time curve is plotted in FIG. 1.

The spread of the pellets after disintegration of the capsule wasconsiderable and varied between subjects. However, a substantialproportion of the bioavailability occurred when the majority of thecoated pellets had reached the ileo-caecal junction and proximal colon,illustrated in FIG. 2 for one of the subjects.

The amount of prednisolone recovered from pellets harvested from thefaeces was low and similar in all subjects, averaging 2.5±1.12 mg andbeing less than 5% of the administered dose in all cases.

Example 4

Second Phase I Study of Colon Targeting—Example According to theInvention

The trial comprised a combined gamma scintigraphic and pharmacokineticstudy with excreted pellet analysis to the same design as the firstPhase I study (above) following administration of the prednisolonesodium metasulphobenzoate ester at a dose of 94.2 mg, equivalent to 60mg of prednisolone. In this second study, the thickness of the coatingof the pellets was increased and the proportion of amylose was increasedin the coat. This reduced drug release and consequent absorption in thesmall intestine, and gave improved colon targeting through an enhancedopportunity for digestion by colonic microbial amylases. Comparison ofprednisolone C_(max) and AUC from two formulations with a conventionalenema. C_(max) AUC Study Compound Dose, route ng/ml ng · ml · h 1stPhase 1 Prednisolone 60 mg, oral 168 ± 56 1441 ± 541Amylose:Ethlycellulose metasulphobenzoate 1:5, Weight Gain 10% 2nd Phase1 Prednisolone 60 mg, oral  54 ± 15  395 ± 105 Amylose:Ethylcellulosemetasulphobenzoate 1:4 Weight Gain 20% McIntyre et al Prednisolone 60mg, rectal 147 ± 79  632 ± 509 1985 metasulphobenzoate

The peak prednisolone plasma levels, determined over 24 hours, weresignificantly lower than those determined in the previous study. Thisreduction in plasma level is a consequence of more specific colonictargeting with lower release in the ileum, due to the coat reformulationand increase in coat weight on the pellets.

Comparisons of plasma level data and gamma scintigraphy images in FIG. 3show that the majority of the limited drug absorption occurred at orafter the ileo-caecal junction, confirming that the coating of thepresent invention provides an optimal effective and specific colonicdelivery system.

As in the first Phase I study, the time to peak plasma levels of drugcoincided almost exactly with arrival of the drug pellets at theileo-caecal junction (5.9±0.4 hours vs 5.9±2.0 hours) with rather morevariation in arrival time, again reflecting the variable transit time ofpellets within the gastro-intestinal tract. This was again indicative ofcolonic release, regardless of transit time, through amylose digestion.

Despite the low systemic bioavailability in the second Phase I study,the quantity of prednisolone harvested from excreted pellets in thefaeces was low in all subjects as with the first Phase I study. The meanquantity of drug excreted in the pellets was 1.7 mg+0.37, determined asprednisolone sodium metasulphobenzoate, this being less than 2% of theadministered dose. This suggests that the vast majority of prednisolonemetasulphobenzoate had been released, and was available, for localaction in the colon.

Example 5

Third Phase I Study

The trial comprised a combined gamma scintigraphic and pharmacokineticstudy with excreted pellet analysis to the same design as the firstPhase I study (above) following administration of prednisolone sodiummetasulphobenzoate ester at a dose of 94.2 mg, equivalent to 60 mgprednisolone. In this third study, administering the coated prednisolonepellets to volunteers in the fed and fasted state was examined. Thepresence of food increased gastrointestinal transit time. Comparison ofprednisolone C_(max) and AUC from the Third Phase 1 Study (Amylose:Ethylcellulose 1:4, 20% Coat Weight Gain) C_(max) AUC Study CompoundDose, route ng/ml ng · ml · h 3^(rd) phase I Prednisolone 60 mg, oral 17213 Fed metasulphobenzoate 3^(rd) phase I Prednisolone 60 mg, oral 14185 Fasted metasulphobenzoate

Administration of the dosage form with food had no effect on the initialdisintegration of the capsule in the stomach. Gastrointestinal transittimes were extended in the fed state compared to the fasted state (Tablebelow). Gastrointestinal Transit for Radiolabelled Pellets Time (hours)Pellet Transit Fasted Fed Profile Mean SD Median Mean SD Median ICJArrival 4.67 2.10 4.36 4.52 3.42 2.82 ICJ Complete 6.90 1.90 6.63 7.862.25 7.00 Colon Arrival 5.57 2.31 4.65 6.34 2.81 6.02 Colon 10.72 4.499.40 13.85 6.01 11.69 Complete

Release of drug, as indicated by a rise in plasma levels, occurred whenthe pellets reached the ileocaecal junction (ICJ) or ascending colon(FIG. 4), regardless of the time taken to reach this location and thefeeding state.

Despite the low plasma levels observed in this study, excreted pelletanalysis showed that, in both the fed and fasted study, over 90% of thedrug content of the formulation had been released from the pellets andwas available for local action in the colon. The mean value for theprednisolone sodium metasulphobenzoate retained in the excreted pelletsfrom the fasted study was 6.1±1.0 mg and in the fed study the value was3.1±1.2 mg.

Example 6

Fourth Phase I Study

The pellets were produced as described in Example 2.

This trial used a higher dose of prednisolone sodium metasulphobenzoate,equivalent to 100 mg of prednisolone. The increase in dose producedlittle effect on the peak plasma level or the area under the plasmacurve, when compared to the previously administered 60 mg dose. Thisstudy indicates that higher doses may be used to deliver prednisolone tothe colon, with low systemic absorption and consequent low risk ofsystemic adverse events. Comparison of prednisolone C_(max) and AUC fromthe Fourth Phase 1 Study C_(max) AUC Study Compound Dose, route ng/ml ng· ml · h 4^(th) phase I Prednisolone 100 mg, 18.9 152 Fastedmetasulphobenzoate oralDiscussion

The present invention is a new formulation which provides good targetedrelease of prednisolone sodium metasulphobenzoate to the colon, with lowsystemic exposure. This formulation thus allows the treatment andprevention of Inflammatory Bowel Diseases, such as ulcerative colitisand Crohn's disease with prednisolone sodium metasulphobenzoate, withoutsystemic side effects The present formulation provides an improvedcolonic delivery system over the known art.

1. A controlled release formulation comprising prednisolone sodiummetasulphobenzoate surrounded by a coating comprising glassy amylose,ethyl cellulose and dibutyl sebacate, wherein the ratio of amylose toethyl cellulose is from 1:3.5 to 1:4.5 and wherein the amylose is cornor maize amylose.
 2. A formulation, as claimed in claim 1, wherein theprednisolone sodium metasulphobenzoate is admixed with a filler.
 3. Aformulation, as claimed in claim 2, wherein the filler is mannitol orlactose.
 4. A formulation, as claimed in any one of claims 1 to 3,wherein the coating thickness is 15 to 25% of the total weight of theformulation.
 5. A formulation, as claimed in any one of claims 1 to 3,which is the form of a pellet, tablet, mini-tab or capsule.
 6. Aformulation, as claimed in any one of claims 1 to 3, which is from 0.5to 1.5 mm in diameter.
 7. A formulation, as claimed in any one of claims1 to 3, wherein the ratio of amylose, ethyl cellulose and dibutylsebacate is in the range of 1:3.5 to 4.5:0.5 to 1.5.
 8. A process forproducing a formulation, the process comprising admixing glassy amylose,ethyl cellulose and dibutyl sebacate and applying the admixture as acoating to a core of prednisolone sodium metasulphobenzoate, wherein theratio of amylose to ethyl cellulose in the formulation is from 1:3.5 to1:4.5 and wherein the amylose is corn or maize amylose.
 9. A method forpreventing or treating Inflammatory Bowel Disease, the method comprisingadministering to a patient a formulation as claimed in claim
 1. 10. Useof glassy amylose, ethyl cellulose, dibutyl sebacate and prednisolonesodium metasulphobenzoate, in the manufacture of a medicament for theprevention or treatment of Inflammatory Bowel Disease.
 11. Aformulation, as claimed in any one of claims 1 to 3, wherein theformulation is within a capsule.
 12. A formulation, as claimed in claim11, wherein the capsule comprises one or more of gelatin, starch orhydroxypropylmethyl cellulose.
 13. A formulation, as claimed in claim 4,wherein the ratio of amylose, ethyl cellulose and dibutyl sebacate is inthe range of 1:3.5 to 4.5:0.5 to 1.5.
 14. A formulation, as claimed inclaim 5, wherein the ratio of amylose, ethyl cellulose and dibutylsebacate is in the range of 1:3.5 to 4.5:0.5 to 1.5.
 15. A formulation,as claimed in claim 6, wherein the ratio of amylose, ethyl cellulose anddibutyl sebacate is in the range of 1:3.5 to 4.5:0.5 to 1.5.
 16. Aprocess, as claimed in claim 8, wherein the prednisolone sodiummetasulphobenzoate is admixed with a filler.
 17. A process, as claimedin claim 16, wherein the filler is mannitol or lactose.
 18. A process,as claimed in any one of claims 8, 16 or 17, wherein the coatingthickness is 15 to 25% of the total weight of the formulation.
 19. Aprocess, as claimed in any one of claims 8, 16 or 17, wherein theformulation is the form of a pellet, tablet, mini-tab or capsule.
 20. Aprocess, as claimed in any one of claims 8, 16 or 17, wherein theformulation is from 0.5 to 1.5 mm in diameter.
 21. A process, as claimedin any one of claims 8, 16 or 17, wherein the ratio of amylose, ethylcellulose and dibutyl sebacate in the formulation is in the range of1:3.5 to 4.5:0.5 to 1.5.
 22. A process, as claimed in claim 18, whereinthe ratio of amylose, ethyl cellulose and dibutyl sebacate in theformulation is in the range of 1:3.5 to 4.5:0.5 to 1.5.
 23. A process,as claimed in claim 19, wherein the ratio of amylose, ethyl celluloseand dibutyl sebacate in the formulation is in the range of 1:3.5 to4.5:0.5 to 1.5.
 24. A process, as claimed in claim 20, wherein the ratioof amylose, ethyl cellulose and dibutyl sebacate in the formulation isin the range of 1:3.5 to 4.5:0.5 to 1.5.
 25. A method, as claimed inclaim 9, wherein the prednisolone sodium metasulphobenzoate is admixedwith a filler.
 26. A method, as claimed in claim 25, wherein the filleris mannitol or lactose.
 27. A method, as claimed in any one of claims 9,25 or 26, wherein the coating thickness is 15 to 25% of the total weightof the formulation.
 28. A method, as claimed in any one of claims 9, 25or 26, wherein the formulation is the form of a pellet, tablet, mini-tabor capsule.
 29. A method, as claimed in any one of claims 9, 25 or 26,wherein the formulation is from 0.5 to 1.5 mm in diameter.
 30. A method,as claimed in any one of claims 9, 25 or 26, wherein the ratio ofamylose, ethyl cellulose and dibutyl sebacate in the formulation is inthe range of 1:3.5 to 4.5:0.5 to 1.5.
 31. A method, as claimed in claim27, wherein the ratio of amylose, ethyl cellulose and dibutyl sebacatein the formulation is in the range of 1:3.5 to 4.5:0.5 to 1.5.
 32. Amethod, as claimed in claim 28, wherein the ratio of amylose, ethylcellulose and dibutyl sebacate in the formulation is in the range of1:3.5 to 4.5:0.5 to 1.5.
 33. A method, as claimed in claim 29, whereinthe ratio of amylose, ethyl cellulose and dibutyl sebacate in theformulation is in the range of 1:3.5 to 4.5:0.5 to 1.5.